Over the past decade, concerns for the substantial increase in the prevalence of allergy have attracted much attention throughout the world. Food allergy affects as much as 25% of the population of Western countries and 8% of children under three years of age and approximately 2% in adults. The continued development and increasing number of cases of allergy, particularly to various food products, have raised serious concerns in the medical community. Recent studies have revealed an increase in hypersensitivity to allergen, particularly oral allergen, in patients with impaired gastrointestinal functions, particularly those with impaired gastrointestinal digestion and/or increased intestinal permeability or gastrointestinal barrier dysfunction, e.g., non-allergic inflammatory disease of the gastrointestinal tract, pharmacological agents that impair gastrointestinal digestion or concomitant gastrointestinal allergy. Allergy-associated gastrointestinal disease often gives rise to symptoms that can easily be confused with non-allergic gastrointestinal disease, e.g., vomiting, nausea, diarrhea, abdominal cramping, dyspepsia, gastro-esophageal reflux, heart burn, or difficulty in swallowing. Use of antacids to treat heart burn, for example, may promote the development of new allergy and delay the initiation of therapy appropriate for the underlying disease e.g., eosinophilic esophagitis. There is an urgent need for new treatments or prevention of allergy, particularly in those more susceptible to developing new allergy.
In allergic disease, platelet-activating factor has been recognized as an important mediator in the pathogenesis of allergic diseases, and Nakamura showed that ketotifen suppresses PAF production. Vadas et al. also showed that serum PAF levels were directly correlated with anaphylaxis.
Dehlink et al., have reported that gastrointestinal diseases such as primary eosinophilic gastrointestinal disorders (EGIDS) as being some form of allergic disorder. EGIDS include eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, and eosinophilic colitis. Patients with such diseases have concomitant IgE-mediated allergies to food and aeroallergen. Much data supporting pathogenic implications of IgE-mediated allergies for eosinophilic esophagitis has been demonstrated, but data for other EGID diseases having a role of IgE have been limited. Dehlink notes a role in the pathology of EGID diseases involving a high affinity receptor for IgE, FcεRI, which has been implicated in IgE-mediated immune activation. Also, FcεRI-mediated immune activation may be mediated by IgE-independent mechanism. This mechanism may be relevant for the pathology of EGIDS in patients lacking elevated serum IgE levels or symptoms attributable to specific allergens. In allergic diseases, platelet-activating factor has been implicated in the pathogenesis of allergic diseases such as bronchial asthma.
The esophagus is normally devoid of eosinophils, but in eosinophilic esophagitis, infiltration of eosinophils occurs, due to conditions such as food allergy, infection, gastro-esophageal reflux disease (GERD) or systemic eosinophilic conditions, for example. Yan et al., suggests treatment options to include specific food avoidance, topical corticosteroids, systemic corticosteroids, leukotriene inhibitors, and biologic treatment and thus suggest that the link between allergy and eosinophilic esophagitis. Remirez et al, further confirms this suggestion, by showing that a patient with eosinophilic esophagitis, had clinical relief upon elimination of diet including eggs upon treatment with ketotifen, a mast cell stabilizer, and montelukast, for example. However, easier administration means are needed. Other scientists such as Katzka et al., further conclude that eosinophilic esophagitis is an allergy-based disorder.
Woerly et al., notes that eosinophils are major effector cells in various allergic diseases and asthma, and suggests that drugs modulating various aspects of eosinophil function such as ketotifen play a role in the treatment of allergic eye diseases by inhibiting chemotaxis, thus suggesting a higher local concentration of drug to mucosa or submucosa may be beneficial.
Moreover, timing of food hypersensitivity may be critical. For example, Paschoal et al., noted that normal mice which eat peanuts are tolerant, but if they were immunized with peanut proteins prior to a challenge diet containing peanuts, the mice developed inflammation. Paschoal et al., also showed that introducing a new protein such as ovalbumin in mice immunized with peanut protein before commencing a 4 week peanut challenge diet induced tolerance, while introducing ovalbumin later in the challenge period induced greater protein antibody levels.
Also, certain substances may promote sensitization and inhibit tolerance of a previously tolerant compound. For example, Brunner et al., showed that co-administrating an anti-acid compound such as sucralfate, or aluminum, a component of sucralfate, with ovalbumin caused sensitization to previously tolerated ovalbumin, via elevation of the gastric pH and more so when administrated in conjunction with aluminum, a known adjuvant. The anti-acid compound and aluminum had shifted the immune response to a Th2 humoral immune response.
There needs to be improved methods of preventing unintended development of new sensitization to allergen, as well as treating and preventing symptoms of and inflammation in patients with allergy associated gastrointestinal and esophageal disease or conditions.